Pharmaceutical formulation

ABSTRACT

Disclosed are aqueous pharmaceutical compositions which provide sustained released delivery of corticosteroid compounds. The pharmaceutical composition comprises an insoluble corticosteroid; a soluble corticosteroid; and at least one viscosity enhancing agent. Also provided are methods for using the pharmaceutical compositions in an epidural injection, intra-articular injection, intra-lesional injection, or an intra-ocular injection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit from U.S. Provisional Application Ser.No. 61/755,723, filed Jan. 23, 2013, and U.S. Provisional ApplicationSer. No. 61/776,617, filed Mar. 11, 2013, the disclosures of which areincorporated herein by reference in their entirety.

FIELD OF INVENTION

The present application relates to a pharmaceutical compositioncomprising both an insoluble form and a soluble form of a corticosteroidin water. The pharmaceutical composition is suitable for localadministration such as epidural injection, intra-articular injection,and intra-lesional injection, and intra-ocular injection.

BACKGROUND OF THE INVENTION

In the spine, the epidural space (also known as “extradural space” or“peridural space”) is the outermost part of the spinal canal. It is thespace within the canal (formed by the surrounding vertebrae) lyingoutside the dura mater (which encloses the arachnoid mater, subarachnoidspace, the cerebrospinal fluid, and the spinal cord). In humans, theepidural space contains lymphatics, spinal nerve roots, loose fattytissue, small arteries, and a network of large, thin-walled bloodvessels called the epidural venous plexus.

An epidural steroid injection is a minimally invasive procedure that canhelp relieve neck, arm, back, and leg pain in an individual caused byinflamed spinal nerves. For instance, an epidural steroid injection maybe performed to relieve pain caused by spinal stenosis, spondylolysis,or disc herniation in an individual. Medicines are delivered to thespinal nerve through the epidural space, the area between the protectivecovering (dura) of the spinal cord and vertebrae. Corticosteroidinjections can reduce inflammation and can be effective when delivereddirectly into the painful area of the individual.

Prednisolone is a cortico steroid drug with predominant glucocorticoidand low mineralocorticoid activity, making it useful for the treatmentof a wide range of inflammatory and auto-immune conditions such asasthma, uveitis, pyoderma gangrenosum, rheumatoid arthritis, ulcerativecolitis, temporal arteritis and Crohn's disease, Bell's palsy, multiplesclerosis, cluster headaches, vasculitis, acute lymphoblastic leukemiaand autoimmune hepatitis, systemic lupus erythematosus, Kawasaki diseaseand dermatomyositis.

Methylprednisolone is typically used for its anti-inflammatory effects.The list of medical conditions for which methylprednisolone isprescribed is rather long, and is similar to other corticosteroids suchas prednisolone. Common uses include arthritis therapy and short-termtreatment of bronchial inflammation or acute bronchitis due to variousrespiratory diseases. It is used both in the treatment of acute periodsand long-term management of autoimmune diseases, most notably systemiclupus erythematosus. It is also used as a treatment for multiplesclerosis.

Dexamethasone is a potent synthetic member of the glucocorticoid classof steroid drugs. It acts as an anti-inflammatory and immunosuppressant.Dexamethasone is used to treat many inflammatory and autoimmuneconditions, such as rheumatoid arthritis and bronchospasm. Dexamethasonemay also be used to treat idiopathic thrombocytopenic purpura, which isa decreased number of platelets due to an immune problem.

Triamcinolone acetonide is a synthetic corticosteroid with markedanti-inflammatory action. Kenalog®-10 Injection (triamcinolone acetonideinjectable suspension, USP) is triamcinolone acetonide, in a sterileaqueous suspension suitable for intralesional and intra-articularinjection, and not suitable for intravenous, intramuscular, intraocular,epidural, or intrathecal use. Each mL of the sterile aqueous suspensionprovides 10 mg triamcinolone acetonide, with sodium chloride forisotonicity, 0.9% (w/v) benzyl alcohol as preservative, 0.75%carboxymethylcellulose sodium, and 0.04% polysorbate 80; sodiumhydroxide or hydrochloric acid may have been added to adjust pH between5.0 and 7.5.

Betamethasone is a potent glucocorticoid steroid with anti-inflammatoryand immunosuppressive properties. Betamethasone is used to treat theinflammation, swelling, and pain of arthritis. CELESTONE® SOLUSPAN®(betamethasone injectable suspension) Injectable Suspension is a sterileaqueous suspension containing 3 mg/mL betamethasone sodium phosphate, 3mg/mL betamethasone acetate, 7.1 mg/mL dibasic sodium phosphate, 3.4mg/mL monobasic sodium phosphate, 0.1 mg/mL edetate disodium, and 0.2mg/mL benzalkonium chloride as preservative. The pH is between 6.8 and7.2. CELESTONE® SOLUSPAN® is used for intra-articular administration andintralesional administration.

Existing pharmaceutical compositions may have immediate or short-termeffects on alleviating pain. This may be sufficient for purposes ofshort-term administration such as to overcome an acute episode orexacerbation of pain. However, such formulations may require repeatedadministration, especially for sustained or chronic pain. In addition,for localized pain, epidural injections that result in the diffusion ofthe active ingredient outside of the target area may be undesirable andmay increase the need for an overall higher dose to ensure that thetarget area is exposed to an effective dose. Furthermore, pharmaceuticalcompositions and methods of administration that contribute to unintendedplacement of the composition can lead to undesirable effects such asarachnoditis caused from an epidural injection.

There exists a need for an improved pharmaceutical composition that canprovide a quick onset of action as well as a long lasting effect; havephysical characteristics that facilitate injection into various parts ofthe body; and be shelf-stable. In particular, a stable, long-actingpharmaceutical composition suited for epidural, intra-articular,intra-lesional or intra-ocular injection is desirable.

SUMMARY OF THE INVENTION

In one aspect, the application discloses an aqueous pharmaceuticalcomposition comprising an insoluble corticosteroid; a solublecorticosteroid; and at least one viscosity enhancing agent; having atleast one of the features selected from the group consisting of: 1) theinsoluble form of the corticosteroid has an average particle size ofless than 10 μm; and 2) the pharmaceutical composition has a viscosityof between 1 kcP and 200 kcP.

In one embodiment, the application discloses an aqueous pharmaceuticalcomposition, wherein the insoluble and soluble corticosteroid areselected from the group consisting of dexamethasone, methylprednisolone,prednisolone, triamcinolone acetonide, betamethasone, and salts andesters thereof. In another embodiment, the soluble corticosteroid isselected from the group consisting of dexamethasone sodium phosphate,methylprednisolone sodium succinate, prednisolone sodium succinate,triamcinolone acetonide phosphate ester, betamethasone sodium phosphate;and the insoluble corticosteroid is selected from the group consistingof dexamethasone acetate, methylprednisolone acetate, prednisoloneacetate, triamcinolone acetonide acetate and betamethasone acetate. Inyet another embodiment, the soluble corticosteroid is dexamethasonesodium phosphate and the insoluble corticosteroid is dexamethasoneacetate.

In one embodiment, at least one viscosity enhancing agent is selectedfrom the group consisting of sodium hyaluronate, hyaluronic acid,cross-linked hyaluronic acid, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxethyl cellulose, andglycerol.

In another embodiment, the ratio of insoluble corticosteroid to solublecorticosteroid ranges from about 1:4 to 4:1. In some embodiments, theaqueous pharmaceutical composition comprises less than 2% w/v of theviscosity enhancing agent. In yet further embodiments, the aqueouspharmaceutical composition further comprises a preservative and/or ananesthetic.

In another aspect, the application provides a method for treatinginflammation and/or pain in an individual in need thereof, comprisinginjecting into an individual an aqueous pharmaceutical compositiondisclosed herein. In one embodiment, the aqueous pharmaceuticalcomposition is injected into the epidural space. In a furtherembodiment, less than 20 N of force is used to inject the aqueouspharmaceutical composition into the epidural space at a rate of about0.5″/min. In yet another embodiment, the individual is injected with theaqueous pharmaceutical composition once every 4 to 24 weeks. In someembodiments, the insoluble form of the corticosteroid has an averageparticle size of less than 20 μm. In some embodiments, the formulationhas a viscosity of between 1 kcP and 200 kcP. In some embodiments, theinsoluble and soluble corticosteroid is selected from the groupconsisting of dexamethasone, methylprednisolone, prednisolone, andtriamcinolone or salts and esters thereof. In further embodiments, thesoluble form of the corticosteroid is selected from the group consistingof dexamethasone sodium phosphate, methylprednisolone sodium succinate,prednisolone sodium succinate, and triamcinolone acetonide phosphateester; and the insoluble form of the corticosteroid is selected from thegroup consisting of dexamethasone acetate, methylprednisolone acetate,prednisolone acetate, and triamcinolone acetonide acetate. In yet otherembodiments, the at least one viscosity enhancing agent is selected fromthe group consisting of sodium hyaluronoate, hyaluronic acid,cross-linked hyaluronic acid, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxethyl cellulose, andglycerol. In certain embodiments, the ratio of insoluble corticosteroidto soluble corticosteroid ranges from about 1:4 to 4:1. In otherembodiments, the aqueous pharmaceutical composition comprises less than2% of the viscosity enhancing agent. In further embodiments, the aqueouspharmaceutical composition further comprises a preservative and/or ananesthetic.

In yet another aspect, the application provides a syringe comprising anaqueous pharmaceutical composition disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows particle size distribution of test samples 1 (1A), 2 (1B),and 3 (1C); and marketed samples 1 (1D), 2, (1E) and 3 (1F).

FIG. 2 shows photomicrographs of test samples 1-3 and marketed products.

FIG. 3 shows a photograph of an exemplary setup for a spreadabilitytest.

FIG. 4 summarizes spreadability results and the surface area of the wetzones on the cotton pad as a function of time for test samples 1-3.

FIG. 5 shows a photograph of the three test samples in triplicate andsummarizes the vertical travel time.

FIG. 6 shows a photograph of an exemplary setup for dissolution testing.

FIG. 7 shows a plot of the percentage of dexamethasone sodium phosphate(7A) and dexamethasone acetate (7B) dissolved as a function of time foreach of test samples 1-3.

FIG. 8 shows the relationship between viscosity and shear force forvarious formulations that vary by sodium hyaluronate molecular weightand concentration.

FIG. 9 shows the relationship between viscosity and shear force forvarious formulations that vary by sodium hyaluronate concentration (MW1.56 MDa).

FIG. 10 shows photographs of formulations in a test tube that vary from0.1% w/v to 1.50% w/v of sodium hyaluronate (1.56 MDa) after 90 minutesof centrifugation at 3500 rpm.

FIG. 11 shows an image of formulations in a test tube that vary from0.75% w/v to 1.5% w/v of sodium hyaluronate (1.56 MDa) after 360 minutesof centrifugation at 3500 rpm.

DETAILED DESCRIPTION OF THE INVENTION

The present application is directed to a pharmaceutical compositioncomprising both an insoluble form and a soluble form of a corticosteroidin water. The pharmaceutical composition is suitable for localadministration such as epidural injection, intra-articular injection,and intra-lesional injection, and intra-ocular injection. Suitablecorticosteroids for the present application include methylprednisolone,dexamethasone, predinisolone, triamcinolone acetonide, andbetamethasone; as well as salts or esters thereof.

The inventor has discovered the advantages of combining both aninsoluble form and a soluble form of a corticosteroid in apharmaceutical composition for a local injection. The local injection ofa soluble form may provide a rapid onset but short duration of actionwhen compared with less soluble preparations. A steroid in a solubleform provides quick action on a target site such as inflamed nerves andtissues, while a steroid in an insoluble form likely becomes availableslowly for action while providing a longer lasting effect. The longlasting effect may allow a steroid to be injected periodically insteadinjected daily, which is difficult to do via epidural or intra-articularadministration. The pharmaceutical composition of the presentapplication may provide a quick onset of action and a long lastingeffect.

Corticosteroids

Soluble Form of the Corticosteroid.

Non-limiting examples of corticosteroids include dexamethasone,methylprednisolone, prednisolone, and triamcinolone acetonide, and saltsor esters thereof. A soluble corticosteroid, as provided herein,provides an immediate or fast-acting effect after being administered toan individual. The soluble corticosteroid may possess a range ofsolubilities, however, it is soluble enough to be dissolved in thepharmaceutical formulation. The solubility of the corticosteroid isdetermined in part by its chemical form, such as salts or esters.Soluble forms of corticosteroids include salts thereof, such as sodium,phosphate, succinate, and combinations thereof.

Non-limiting examples of soluble corticosteroids include dexamethasonesodium phosphate, methylprednisolone sodium succinate, prednisolonesodium succinate, triamcinolone acetonide phosphate ester, andbetamethasone sodium phosphate.

Insoluble Form of the Corticosteroid.

An insoluble corticosteroid, as provided herein, provides a delayed orlong-acting effect after being administered to an individual. As usedherein, an “insoluble corticosteroid” may possess a range ofsolubilities, and in some embodiments, the insoluble corticosteroidexists as a particle in the pharmaceutical formulation. The insolublecorticosteroid is not totally insoluble, but dissolves over time toprovide a source of the drug for the individual after the solublecorticosteroid is no longer available. It is understood that the“soluble” and “insoluble” terms as used herein is meant to describe thetwo forms of the corticosteroid in relative terms and is used todescribe forms of the corticosteroids that provide an immediate anddelayed effect, respectively, after administration to the individual. Insome embodiments, one injection of the insoluble corticosteroid into anindividual, provides a source of corticosteroid for at least about 4,about 6, about 8, about 10, about 12, about 14, about 16, about 18,about 20, about 22, or about 24 weeks. In some embodiments, the sourceof the corticosteroid provides an amount effective to reduce or inhibitinflammation and/or pain.

Non-limiting examples of the insoluble corticosteroid are dexamethasone,methylprednisolone, prednisolone, triamcinolone acetonide, salts andesters thereof. A specific example is an acetate ester of thecorticosteroid. In some embodiments, non-limiting examples of theinsoluble corticosteroid include dexamethasone acetate,methylprednisolone acetate, prednisolone acetate, triamcinoloneacetonide acetate, and betamethasone acetate.

Particle Size of the Insoluble Corticosteroid.

The insoluble corticosteroid may exist as particles suspended anddispersed throughout the pharmaceutical composition. The particle sizeof the insoluble corticosteroid, in combination with other factors suchas temperature, and composition viscosity, may influence the tendency ofthe particles to aggregate, settle, unevenly disperse throughout thepharmaceutical composition. Aggregation of insoluble corticosteroidparticles may change the release profile of the drug.

In some embodiments, the particle size of the insoluble corticosteroidis less than 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 8 μm, 10 μm, or 20 μm. Insome embodiments, the particle of the insoluble corticosteroid isbetween 2 μm and 20 μm, 2 μm and 10 μm, 2 μm and 5 μm, 2 μm and 3 μm, 3μm and 20 μm, 3 μm and 10 μm, 3 μm and 5 μm, 3 μm and 4 μm, 4 μm and 20μm, 4 μm and 10 μm, or 4 μm and 5 μm. In some embodiments, the insolubleparticles is between 0.1 μm and 40 μm, 0.1 μm and 35 μm, 0.1 μm and 30μm, 0.1 μm and 25 μm, 0.1 μm and 20 μm, 0.1 μm and 15 μm, 0.1 μm and 10μm, 2.0 μm and 40 μm, 2.0 μm and 35 μm, 2.0 μm and 30 μm, 2.0 μm and 25μm, 2 μm and 20 μm, 2.0 μm and 15 μm, or 2.0 μm and 10 μm. In someembodiments, the foregoing size range applies to most of the insolubleparticles of the pharmaceutical composition. In some embodiments, theforegoing size range applies to at least 75%, 80%, 85%, 90%, 95%, 98% or99% of the insoluble particles of the pharmaceutical composition.

In some embodiments, the insoluble corticosteroid particles are uniformin size, ±10%. In some embodiments, the insoluble corticosteroidparticles are uniform in size, ±5%.

Ratio Between Soluble and Insoluble Forms.

In general, the insoluble form and soluble form of the steroid are in amolar ratio of about 65-95 to 5-35. The molar ratio of insoluble tosoluble corticosteroid may have a range of 2:1 to 19:1; 2:1 to 10:1; or2:1 to 5:1. In one embodiment, the molar ratio of insoluble to solublecorticosteroid is 65:35, 75:25, 95:5, or 4:1.

In another embodiment, the weight ratio of insoluble to solublecorticosteroid may have a range of 2:1 to 19:1; 2:1 to 10:1; or 2:1 to5:1. In one embodiment, the weight ratio of insoluble to solublecorticosteroid is 65:35, 75:25, 95:5, or 4:1.

In some of the foregoing embodiments, the soluble corticosteroid and theinsoluble corticosteroid are selected from the group consisting of 1)dexamethasone sodium phosphate and dexamethasone acetate; 2)methylprednisolone sodium succinate and methylprednisolone acetate; 3)prednisolone sodium succinate and prednisolone acetate; 4) triamcinoloneacetonide phosphate ester and triamcinolone acetonide acetate; and 5)betamethasone sodium phosphate and betamethasone acetate.

Additional Optional Components.

Viscosity Enhancing Agent.

In one embodiment, a viscosity enhancing agent is included in thepharmaceutical composition. The viscosity enhancing agent provides anadvantage that when the pharmaceutical composition is administered intoa target site (e.g., the epidural space of an individual), theformulation stays longer in the target site due to a low degree ofcirculation of the viscous formulation in the target site. The viscosityenhancing agent may also promote the binding of the active drug to atarget site and to enhance drug absorption and bioavailability locally.

The viscosity of the composition also contributes to the stability ofthe pharmaceutical composition. Higher viscosities may help reducesettling of insoluble particles and improves shelf-life. The viscosityof the composition is in large part influenced by the amount of theviscosity enhancing agent. Higher concentrations of the viscosityenhancing agent compared to lower concentrations results in a higherviscosity. Temperature also affects viscosity, with lower temperaturesresulting in higher viscosities compared to higher temperatures of thesame composition.

Suitable viscosity enhancing agent include sodium hyaluronate,hyaluronic acid, polyvinylpyrrolidone (PVP), cross-linked hyaluronicacid, hydroxypropyl methylcellulose, hydroxypropyl cellulose,hydroxylethyl cellulose, glycerol, or a mixture thereof. Preferredviscosity enhancing agents include sodium hyaluronate,polyvinylpyrrolidone (PVP), sodium hydroxypropyl cellulose, and carboxymethylcellulose. The present formulation does not include polyethyleneglycol due to potential side effects.

The amount of the viscosity enhancing agent is based on the agent used,and is in general in an amount of about 0.05-30% (w/v). In someembodiments, the concentration of the viscosity enhancing agent is about0.1% w/v, about 0.25% w/v, about 0.5% w/v, about 0.75% w/v, about 1.0%w/v, about 1.1% w/v, about 1.15% w/v, about 1.20% w/v, about 1.25% w/v,about 1.30% w/v, about 1.35% w/v, about 1.40% w/v, about 1.45% w/v, orabout 1.5% w/v.

In some embodiments, the concentration of the viscosity enhancing agentis between 0.05% w/v and 1.5% w/v; 0.05% w/v and 0.5% w/v; 0.1% w/v and3.0% w/v; 0.1% w/v and 1.5% w/v; 0.1% w/v and 1.0% w/v; 0.5% w/v and 1%w/v; 0.5% w/v and 2.5% w/v; 1.0% w/v and 3.0% w/v; 1.0% w/v and 1.5%w/v; 1.0% w/v and 1.25% w/v; 1.25% w/v and 1.5% w/v; or 1.5% w/v and3.0% w/v.

In some embodiments, the molecular weight of the viscosity enhancingagent is between 500 kDa and 5.0 MDa; 500 kDa and 3.0 MDa; 500 kDa and2.0 MDa; 500 kDa and 1.0 MDa; 500 kDa and 2.0 MDa; 1.0 MDa and 3.0 MDa;1.0 MDa and 2.5 MDa; 1.0 MDa and 2.0 MDa; and 1.2 MDa and 1.8 MDa. Insome embodiments, the molecular weights of sodium hyaluronate is about711 kDa; about 880 kDa; about 1.56 MDa; about 1.8 MDa and about 2.65MDa. In some of the embodiments, the molecular weight is the numberaverage molecular weight, and in other embodiments the molecular weightis the weight average molecular weight. In some of the foregoingembodiments, the viscosity enhancing agent is sodium hyaluronate. Insome embodiments, the viscosity enhancing agent is hyaluronic acid or apharmaceutically acceptable salt of hyaluronate, such as sodium salt,phosphate salt or calcium salt.

In some embodiments, the viscosity of the pharmaceutical composition isabout 300 kcP, about 250 kcP, about 200 kcP, about 150 kcP, about 140kcP, about 130 kcP, about 120 kcP, about 110 kcP, about 100 kcP, about90 kcP, about 80 kcP, about, 70 kcP, about 40 kcP, about, 30 kcP, about25 kcP, about 20 kcP, about 10 kcP, about 5 kcP, or about 1 kcP.

In some embodiments, the viscosity of the composition is between 1 kcPand 300 kcP; 1 kcP and 100 kcP; 1 kcP and 50 kcP; 1 kcP and 10 kcP; 10kcP and 50 kcP; 10 kcP and 100 kcP; 50 kcP and 100 kcP; 100 kcP and 300kcP; 50 kcP and 200 kcP; 75 kcP and 180 kcP; 100 kcP and 150 kcP; 150kcP and 200 kcP; 200 kcP and 250 kcP; 250 kcP and 300 kcP.

Particle Size and Viscosity Combinations.

In some compositions, the particle size is less than about 2 μm, about 3μm, about 4 μm, about 5 μm, about 6 μm, about 8 μm, about 10 μm, orabout 20 μm, and the viscosity of the formulation is between 1 kcP and300 kcP. In some compositions, the particle size is less than about 2μm, about 3 μm, about 4 μm, about 5 μm, about 6 μm, about 8 μm, about 10μm, or about 20 μm and the viscosity of the formulation is between 1 kcPand 200 kcP. In some compositions, the particle size is less than about2 μm, about 3 μm, about 4 μm, about 5 μm, about 6 μm, about 8 μm, about10 μm, or about 20 μm and the viscosity of the formulation is between 1kcP and 100 kcP. In some compositions, the particle size is less thanabout 2 μm, about 3 μm, about 4 μm, about 5 μm, about 6 μm, about 8 μm,about 10 μm, or about 20 μm and the viscosity of the formulation isbetween 100 kcP and 150 kcP. In some compositions, the particle size isless than about 5 μm, and the viscosity of the formulation is between100 kcP and 150 kcP. In some compositions, the particle size is about 5μm, and the viscosity of the formulation is between 100 kcP and 150 kcP.In some compositions, the particle size is about 5 μm, and the viscosityof the formulation is between 1 kcP and 50 kcP.

In some embodiments, the pharmaceutical composition is a gel. Inalternative embodiments, the pharmaceutical composition is an aqueoussolution.

Buffer.

Suitable buffering agents for use with the pharmaceutical compositionsdisclosed herein include, but are not limited to, organic acid saltssuch as salts of citric acid, ascorbic acid, gluconic acid, carbonicacid, tartaric acid, succinic acid, acetic acid or phthalic acid; Tris,thomethamine hydrochloride, or phosphate buffer. In some embodiments,the buffer is physiologically compatible.

pH.

The pH of the formulation may be inherently provided by the excipientspresent in the formulation; alternatively, a pH adjustment agent may beemployed. A pH adjustment agent such as a buffer or a simple acid orbase can be added to the pharmaceutical composition to maintain the pHto 6-8. For example, the amount of a pH adjusting agent is in general0.1-10%. In some embodiments, the pH of the formulation is withinphysiological range.

Osmolality.

The osmolality of the formulation is between 200 mOsm/kg and 350mOsm/kg, 250 mOsm/kg and 300 mOsm/kg, 280 mOsm/kg and 290 mOsm/kg. Insome embodiments, the osmolality of the formulation is within aphysiological range. In some embodiments, the pharmaceutical compositionis isotonic in a human.

Anesthetic.

In one embodiment, the pharmaceutical composition further comprises ananesthetic agent such as lidocaine, bupivacaine, or benzocaine.

Surfactant.

The present formulation preferably does not include a surfactant.However, in some embodiments, the pharmaceutical composition comprisesone or more non-ionic surfactants. Inclusion of a surfactant increasesthe solubility and wettability of the drug particles. Suitable non-ionicsurfactants include polysorbates (e.g., TWEEN®-80, TWEEN®-20),tyloxapol, polyoxyl castor oil, polaxamers, polyethylene glycol,caprylic triglyceride, polyoxyl stearates (e.g., oxyethylenemonostearate), polyoxyethylated vegetable oils and glycerylmonostearate. A preferred non-ionic surfactant is a polysorbate such asTWEEN®-80. The amount of the non-ionic surfactant in the pharmaceuticalcomposition, if present, is in general 0.001-10, or 0.01-1% (w/v) of thepharmaceutical composition.

Shelf Life.

The term “shelf life” refers to the amount of time the pharmaceuticalcomposition may be stored without loss of potency and/or performanceprofile. In some embodiments, shelf life refers to the amount of timethe pharmaceutical composition may be stored without a loss of more than2,%, 5%, 8% or 10% of the potency and/or performance. Thepreservative-free pharmaceutical compositions provided herein aredesigned to have shelf life of at least 12, 24 or 36 months. In someembodiments, the pharmaceutical compositions have a shelf life ofbetween 12 and 24 months. In some embodiments, the pharmaceuticalcomposition is stored at room temperature and is shelf stable for atleast 12, 24 or 36 months. In some embodiments, the pharmaceuticalcomposition is stored below room temperature and has a shelf life of atleast 12, 24, or 36 months.

Preservatives.

In some embodiments, the pharmaceutical composition further comprises apreservative, such as an anti-microbial preservative, in order toincrease the shelf-life of the pharmaceutical composition. Anypreservative which does not adversely interact with the active drug orany of the excipients may be employed. For example, preservativesinclude ethanol, benzyl alcohol, benzalkonium chloride, benzethoniumchloride, benzoic acid, bronopol, butyl-paraben, cetrimide,chlorhexidine. The amount of preservative may range, for example, fromabout 0.01-1%.

Exemplary Formulations

In one embodiment, the pharmaceutical composition comprises insolublemethylprednisolone acetate and soluble methylprednisolone sodiumsuccinate in an aqueous solution such as water. For example,methylprednisolone acetate is in an amount of 65 to 95%, andmethylprednisolone sodium succinate is in an amount of 5 to 35% of themethylprednisolone equivalent. The dose per injection ofmethylprednisolone is in the range of 20 to 120 mg/dose in 1 to 10 ml ofa sterile solution such as water for injection or saline.

In one embodiment, the pharmaceutical composition comprises insolubleprednisolone acetate and soluble prednisolone sodium succinate in anaqueous solution such as water. For example, prednisolone acetate is inan amount of 65 to 95%, and prednisolone sodium succinate is in anamount of 5 to 35% of the prednisolone equivalent. The dose perinjection for prednisolone is in the range of 20 to 120 mg/dose in 1 to10 ml of a sterile solution such as water for injection or saline.

In one embodiment, the pharmaceutical composition comprises insolubledexamethasone acetate and soluble dexamethasone sodium phosphate in anaqueous solution such as water. For example, dexamethasone acetate is inan amount of 65 to 95% and dexamethasone sodium phosphate is in anamount of 5 to 35% of the dexamethasone equivalent. The dose perinjection of dexamethasone is in the range of 3 to 20 mg/dose in 1 to 10ml of a sterile solution such as water for injection or saline.

Yet in another embodiment, the pharmaceutical composition comprisesinsoluble triamcinolone acetonide acetate and soluble triamcinoloneacetonide phosphate ester in water. For example, triamcinolone acetonideacetate is an amount of 65 to 95% and triamcinolone acetonide phosphateis an amount of 5 to 35% of the triamcinolone equivalent. The dose perinjection of triamcinolone is in the range of 20 mg to 120 mg/dose in 1to 10 ml of a sterile solution such as water for injection or saline.

In one embodiment, the pharmaceutical composition comprises insolublebetamethasone acetate and soluble betamethasone sodium phosphate in anaqueous solution such as water. For example, betamethasone acetate is ina majority amount of 65 to 95% and betamethasone sodium phosphate is ina lesser amount of 5 to 35% of the betamethasone equivalent. The doseper injection of betamethasone is in the range of 3-50, or 3-20, or 6-50mg/dose in 1 to 10 ml of a sterile solution such as water for injectionor saline.

In one embodiment, the aqueous pharmaceutical composition comprises aninsoluble corticosteroid; a soluble corticosteroid; and at least oneviscosity enhancing agent; wherein the aqueous pharmaceuticalcomposition comprises at least one of the features selected from thegroup consisting of: 1) the insoluble form of the corticosteroid has anaverage particle size of less than 10 μm; and 2) the pharmaceuticalcomposition has a viscosity of between 1 kcP and 200 kcP. In someembodiments, the aqueous pharmaceutical composition is in a unit doseand has a volume of 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, or10 mL. In some embodiments, the viscosity enhancing agent concentrationis between 0.05% w/v and 1.5% w/v; 0.05% w/v and 0.5% w/v; 0.1% w/v and1.5% w/v; 0.1% w/v and 1.0% w/v; 0.5% w/v and 1% w/v; 0.5% w/v and 2.5%w/v; 1.0% w/v and 1.5% w/v; 1.0% w/v and 1.25% w/v; or 1.25% w/v and1.5% w/v.

In further embodiments, the aqueous pharmaceutical composition comprisesdexamethasone acetate; dexamethasone phosphate; and sodium hyaluronate;wherein the aqueous pharmaceutical composition comprises at least one ofthe features selected from the group consisting of: 1) the insolubleform of the corticosteroid has an average particle size of less than 10μm; and 2) the pharmaceutical composition has a viscosity of between 1kcP and 200 kcP. In some embodiments, the aqueous pharmaceuticalcomposition is in a unit dose and has a volume of 1 mL, 2 mL, 3 mL, 4mL, 5 mL, 6 mL, 7 mL, 8 mL, or 10 mL.

In further embodiments, the aqueous pharmaceutical composition comprisesdexamethasone acetate; dexamethasone phosphate; and sodium hyaluronate;wherein the aqueous pharmaceutical composition comprises at least one ofthe features selected from the group consisting of: 1) dexamethasoneacetate has an average particle size of less than 10 μm; and 2) thepharmaceutical composition has a viscosity of between 1 kcP and 200 kcP;wherein the sodium hyaluronate concentration is between 0.05% w/v and1.5% w/v; 0.05% w/v and 0.5% w/v; 0.1% w/v and 1.5% w/v; 0.1% w/v and1.0% w/v; 0.5% w/v and 1% w/v; 0.5% w/v and 2.5% w/v; 1.0% w/v and 1.5%w/v; 1.0% w/v and 1.25% w/v; or 1.25% w/v and 1.5% w/v. In someembodiments, the molecular weight of sodium hyaluronate is 500 kDa and2.0 MDa. In other embodiments, the molecular weight of sodiumhyaluronate is 1.2 MDa and 1.8 MDa. In some embodiments, the aqueouspharmaceutical composition is in a unit dose and has a volume of 1 mL, 2mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, or 10 mL.

In further embodiments, the aqueous pharmaceutical composition comprisesdexamethasone acetate; dexamethasone phosphate; and sodium hyaluronate;wherein the aqueous pharmaceutical composition comprises at least one ofthe features selected from the group consisting of: 1) dexamethasoneacetate has an average particle size of about 5 μm; and 2) thepharmaceutical composition has a viscosity of between 1 kcP and 200 kcP;wherein the sodium hyaluronate concentration is between 0.05% w/v and1.5% w/v; 0.05% w/v and 0.5% w/v; 0.1% w/v and 1.5% w/v; 0.1% w/v and1.0% w/v; 0.5% w/v and 1% w/v; 0.5% w/v and 2.5% w/v; 1.0% w/v and 1.5%w/v; 1.0% w/v and 1.25% w/v; or 1.25% w/v and 1.5% w/v. In someembodiments, the molecular weight of sodium hyaluronate is 500 kDa and2.0 MDa. In other embodiments, the molecular weight of sodiumhyaluronate is 1.2 MDa and 1.8 MDa. In some embodiments, the aqueouspharmaceutical composition is in a unit dose and has a volume of 1 mL, 2mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, or 10 mL.

Each of the exemplary formulations in Table 1 comprises a weight ratioof insoluble to soluble corticosteroid of 4:1 and a total corticosteroidweight of 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg per dose. The size of theinsoluble corticosteroid particles is about 5 μm. The molecular weightof the sodium hyaluronate is 1.56 MDa. The formulations further comprisea physiologically compatible buffer solution, such as 15 mM PBSsolution. Each of the formulations are prepared in a 1 mL, 2 mL, 3 mL, 4mL, 5 mL, 6 mL, 7 mL, 8 mL, and 10 mL unit doses.

TABLE 1 Sodium dexamethasone hyaluronate, 1.56 dexamethasone sodium #MDa (% w/v) acetate (mg) phosphate (mg) 1 0.25 4 1 2 0.35 4 1 3 0.50 4 14 0.75 4 1 5 1.0 4 1 6 1.1 4 1 7 1.25 4 1 8 1.3 4 1 9 1.4 4 1 10 1.5 4 111 0.25 8 2 12 0.35 8 2 13 0.50 8 2 14 0.75 8 2 15 1.0 8 2 16 1.1 8 2 171.25 8 2 18 1.3 8 2 19 1.4 8 2 20 1.5 8 2 21 0.25 12 3 22 0.35 12 3 230.50 12 3 24 0.75 12 3 25 1.0 12 3 26 1.1 12 3 27 1.25 12 3 28 1.3 12 329 1.4 12 3 30 1.5 12 3 31 0.25 16 4 32 0.35 16 4 33 0.50 16 4 34 0.7516 4 35 1.0 16 4 36 1.1 16 4 37 1.25 16 4 38 1.3 16 4 39 1.4 16 4 40 1.516 4 41 0.25 24 6 42 0.35 24 6 43 0.50 24 6 44 0.75 24 6 45 1.0 24 6 461.1 24 6 47 1.25 24 6 48 1.3 24 6 49 1.4 24 6 50 1.5 24 6

Each of the formulations listed in Table 1, further optionally containan anesthetic and/or preservative. In some embodiments, the soluble andinsoluble corticosteroids of each of the formulations disclosed in Table1 can be replaced with corticosteroids selected from the groupconsisting of 1) methylprednisolone sodium succinate andmethylprednisolone acetate; 2) prednisolone sodium succinate andprednisolone acetate; 3) triamcinolone acetonide phosphate ester andtriamcinolone acetonide acetate; and 4) betamethasone sodium phosphateand betamethasone acetate.

Packaging and Kits.

The present formulation can be packaged in a unit dose vial or syringe.It can also be packaged in a two-compartment vial or syringe with thesoluble and insoluble steroid each in a separate compartment. In someembodiments, the unit dose is between 1 mL and 10 mL; 2 mL and 8 mL; and2 mL and 5 mL. In some embodiments, the unit dose is about 1 mL, about 2mL, about 2.5 mL, about 3 mL, about 3.5 mL, about 4 mL, about 4.5 mL,about 5 mL, or about 5.5 mL. In any of the foregoing embodiments, theunit dose is a gel pharmaceutical composition. In other foregoingembodiments, the unit dose is an aqueous pharmaceutical composition. Thepresent disclosure also provides for a kit comprising a pharmaceuticalformulation disclosed herein and instructions for use.

In some of the foregoing embodiments, the pharmaceutical composition isaseptic. In some of the foregoing embodiments, the pharmaceuticalcomposition is prepared using aseptic technique. For instance, thevarious components of the composition may be individually sterilized andthen combined under aseptic conditions to provide the sterilepharmaceutical composition. In some of the foregoing embodiments, thepharmaceutical composition is terminally sterilized.

Methods

The present application also provides methods for treating inflammationand/or pain such as those associated with rheumatoid arthritis,osteoarthritis, lower back pain, tendonitis, spinal stenosis, discherniation, radiculitis and chronic discogenic pain with any of theaqueous pharmaceutical compositions disclosed herein.

In one embodiment, the method comprises the steps of identifying anindividual suffering from inflammation and/or pain, and injecting to theepidural space of the individual any of the aqueous pharmaceuticalcompositions disclosed herein. The method optionally comprises a step ofinjecting to the epidural space of the individual an anesthetic agentsuch as lidocaine, bupivacaine, or benzocaine. The anesthetic agent canbe administered in a separate injection or can be combined with theaqueous pharmaceutical composition and injected together.

In another embodiment, the method comprises the steps of identifying anindividual suffering from inflammation and/or pain, and injecting to askin lesion of the individual any of the aqueous pharmaceuticalcompositions disclosed herein. The method optionally comprises a step ofinjecting to the skin lesion of the individual an anesthetic agent. Theanesthetic agent can be administered in a separate injection or can becombined with the aqueous pharmaceutical composition and injectedtogether.

In another embodiment, the method comprises the steps of identifying anindividual suffering from inflammation and/or pain, and injecting to anaffected joint of the individual any of the aqueous pharmaceuticalcompositions disclosed herein. The method optionally comprises a step ofinjecting to the affected joint of the individual an anesthetic agent.The anesthetic agent can be administered in a separate injection or canbe combined with the pharmaceutical composition and injected together.

In some embodiments, the dose of the steroid injected is based on thepotency of the steroid. In some embodiments, the amount ofcorticosteroid administered to an individual in a single dose is between2 mg and 20 mg; 5 mg and 15 mg; and 5 mg and 10 mg. In some embodiments,the amount of corticosteroid administered to an individual in a singledose is about 2 mg, 5 mg, 8 mg, 10 mg, 15 mg and 20 mg.

In certain embodiments, the dosage of dexamethasone is about 3 to 20mg/dose; the dosage of methylprednisolone is about 20 to 120 mg/dose,the dosage of prednisolone is about 20 to 120 mg/dose; the dosage oftriamcinolone acetonide is about 20 to 120 mg/dose. The foregoingdosages represent the total amount of the insoluble and solublecorticosteroid in a dose.

In some embodiments, the individual is injected with the pharmaceuticalcomposition once every 4 to 24 weeks; 6 to 20 weeks; or 8 to 12 weeks.In some embodiments, the individual is injected with the pharmaceuticalcomposition about every 4, 6, 8, 12, 14, 16, 18, or 20 weeks.

The methods and compositions disclosed herein are useful in treating anindividual that is a mammal, such as a human, dog or cat. The methodsand compositions disclosed herein are particularly useful in treatinghumans.

Other Uses.

Intralesional injection is a direct delivery of medicationpercutaneously into skin lesions. Intralesional injections areintroduced into or performed within a lesion. The skin serves as areservoir, allowing medication deposited in the dermis to be deliveredover a period of time, resulting in prolonged therapy while avoiding orminimizing the adverse effects of systemic therapy.

Intra-articular injection is a procedure used in the treatment ofinflammatory joint conditions, such as rheumatoid arthritis, psoriaticarthritis, gout, tendinitis, bursitis and occasionally osteoarthritis. Ahypodermic needle is injected into the affected joint where it deliversan anti-inflammatory agent such as a corticosteroid.

The application discloses pharmaceutical compositions with a range ofviscosities. The choice of the viscosity is in part dependent on thedesired location of the injected pharmaceutical composition in theindividual. For instance, when a localized amount of the pharmaceuticalcomposition is desired, a pharmaceutical composition with a higherviscosity may be selected. Alternatively, if broader coverage of thepharmaceutical composition is desired, a pharmaceutical composition witha lower viscosity may be selected. In some embodiments, the methodcomprises administering the pharmaceutical composition via atransforaminal injection, wherein the pharmaceutical compositioncomprises between 0.75% and 1.5%, 1.0% and 1.5%, or 0.75% and 1.25%, ofa viscosity enhancing agent. In some embodiments, the method comprisesadministering the pharmaceutical composition via an intralaminarinjection, wherein the pharmaceutical composition comprises between 0.1%and 1.5%, 0.1% and 1.0%, 0.1% and 0.75%, 0.1% and 0.5%, 0.1% and 0.25%,0.75% and 1.5%, 1.0% and 1.5%, or 0.75% and 1.25% of a viscosityenhancing agent. In some embodiments, the method comprises administeringthe pharmaceutical composition via a caudal injection, wherein thepharmaceutical composition comprises between 0.1% and 1.5%, 0.1% and1.0%, 0.1% and 0.75%, 0.1% and 0.5%, or 0.1% and 0.25%, of a viscosityenhancing agent. In some of the foregoing embodiments, the viscosityenhancing agent is hyaluronic acid or a salt thereof.

Syringeability and Injectability.

Syringeability is the ability of an injectable therapeutic to passeasily through a hypodermic needle on transfer from a vial prior to aninjection. Syringeability includes such factors as ease of withdrawal,clogging and foaming tendencies, and accuracy of dose measurements.Injectability refers to the performance of the formulation duringinjection. Injectability includes pressure or force required forinjection, evenness of flow, and freedom from clogging (i.e., noblockage of the syringe needle). The syringability and injectability isinfluenced in part by the viscosity of the pharmaceutical composition,the injection or transfer flow rate, and the needle characteristics(such as length and gauge).

Desirable characteristics of injectability include, for example, asmooth and continuous injection without undue force. Such in injectionallows the person administrating the injection to maintain continuouscontrol over the procedure without incurring undue strain.

The application discloses compositions that are easily syringeableand/or injectable into an individual. The application also disclosesmethods for injecting an individual with a pharmaceutical composition,wherein the injecting is easy and provides a continuous flow of thepharmaceutical composition. In some embodiments, the method comprisesapplying an injecting force of between 5 N and 90 N, 5 N and 50 N, 50Nand 100 N, 5 N and 25 N, 25 N and 50 N, or 10 N and 40 N to the syringe.In some embodiments, the method comprises applying a force of no morethan 5 N, no more than 7 N, no more than 10 N, no more than 15 N, nomore than 17, no more than 21 N, no more than 27 N, no more than 29 N,no more than 33 N, no more than 38 N, no more than 39 N, no more than 46N, no more than 59 N, no more than 70, no more than 78 N or no more than90 N to the syringe. In some embodiments, the method comprises applyinga force of about 5 N, about 7 N, about 10 N, about 15 N, about 17, about21 N, about 27 N, about 29 N, about 33 N, about 38 N, about 39 N, about46 N, about 59 N, about 70, about 78 N or about 90 N to the syringe. Insome embodiments, the injection force results in the injection of thepharmaceutical composition at a rate of about 0.4″/min, about 0.5″/min,about 0.6″/min, about 0.7″/min, about 0.8″/min, about 0.9″/min, about1.0″/min, about 1.1″/min, about 1.2″/min, about 1.3″/min, about1.4″/min, about 1.5″/min, about 1.75″/min, about 2.0″/min, about2.25″/min, or at about 2.36″/min.

In any of the foregoing embodiments, the syringe comprises a needlehaving needle gauge of 19, 20, 21, 22, 23, 24, or 25.

The application discloses method for injection which reduces the“stringing effect”. The stringing effect refers to a phenomenon thatwhen the injection of the pharmaceutical composition into an individualis finished, the remaining composition in the bore of the needle used inthe injection comes into contact with the individual. For instance, whenthe needle is withdrawn from the target site, the remaining compositionin the bore of the needle is drawn out due to the viscous nature of thecomposition and elongates like string. The needle may leave a trail ofthe composition as it exits the individual, potentially exposingunintended areas and tissues to the composition. Unintended placement ofthe composition can lead to undesirable effects such as arachnoditiscaused from an epidural injection. In some instances, upon withdrawal ofthe needle the composition injected into the target site may elongateand stretch and may come into contact with unintended areas and tissuesof the individual.

In some embodiments, the methods and compositions disclosed hereinreduce the occurrence of the stringing effect. In some embodiments, uponwithdrawal from the injection site, no pharmaceutical compositiondisclosed herein exits the needle into the individual. In someembodiments, the pharmaceutical composition enters an individual onlywhen an injection force is applied. In some embodiments, the compositionmakes a clean break with very little stringing upon separation ordivision.

In some embodiments, the application discloses a method for treatinginflammation and/or pain in an individual in need thereof, comprisinginjecting an aqueous pharmaceutical composition disclosed herein intothe epidural, intralesional, intra-articular or ocular space of theindividual; and wherein the method comprises one or more of the stepsselected from the group consisting of 1) applying a force of less than 5N, less than 7 N, less than 10 N, less than 15 N, less than 17, or lessthan 21 N to inject the aqueous pharmaceutical composition at a rate ofabout 0.4″/min, about 0.5″/min, about 0.6″/min, about 0.7″/min, about0.8″/min, about 0.9″/min, about 1.0″/min, about 1.1″/min, about1.2″/min, about 1.3″/min, about 1.4″/min, about 1.5″/min, about1.75″/min, about 2.0″/min, about 2.25″/min, or at about 2.36″/min.; and2) injecting the aqueous pharmaceutical composition once every 4 to 24weeks.

In some embodiments, the application discloses a method for treatinginflammation and/or pain in an individual in need thereof, comprisinginjecting an aqueous pharmaceutical composition disclosed herein intothe epidural, intralesional, intra-articular or ocular space of theindividual; and wherein the method comprises one or more of the stepsselected from the group consisting of 1) applying a force of less than21 N to inject the aqueous pharmaceutical composition at a rate of about0.5″/min; and 2) injecting the aqueous pharmaceutical composition onceevery 4 to 24 weeks.

In some embodiments, the application discloses a method for treatinginflammation and/or pain in an individual in need thereof, comprisinginjecting any of the exemplary formulations in Table 1 into theepidural, intralesional, intra-articular or ocular space of theindividual; and wherein the method comprises one or more of the stepsselected from the group consisting of 1) applying a force of less than 5N, less than 7 N, less than 10 N, less than 15 N, less than 17, or lessthan 21 N to inject the aqueous pharmaceutical composition at a rate ofabout 0.4″/min, about 0.5″/min, about 0.6″/min, about 0.7″/min, about0.8″/min, about 0.9″/min, about 1.0″/min, about 1.1″/min, about1.2″/min, about 1.3″/min, about 1.4″/min, about 1.5″/min, about1.75″/min, about 2.0″/min, about 2.25″/min, or at about 2.36″/min.; and2) injecting the aqueous pharmaceutical composition once every 4 to 24weeks. In further embodiments, the step of injecting the aqueouspharmaceutical composition occurs about every 4, 6, 8, 12, 14, 16, 18,or 20 weeks.

In some embodiments, the application discloses a method for treatinginflammation and/or pain in an individual in need thereof, comprisinginjecting any of the exemplary formulations in Table 1 into the epiduralspace of the individual; and wherein the method comprises one or more ofthe steps selected from the group consisting of 1) applying a force ofless than 21 N to inject the aqueous pharmaceutical composition at arate of about 0.5″/min; and 2) injecting the aqueous pharmaceuticalcomposition once every 4 to 24 weeks. In further embodiments, the stepof injecting the aqueous pharmaceutical composition occurs about every4, 6, 8, 12, 14, 16, 18, or 20 weeks.

In some embodiments, the application discloses the use of an aqueouspharmaceutical composition, as described herein, in the manufacture of aformulation for the treatment of inflammation and/or pain in anindividual in need thereof, wherein the formulation is injected into theindividual.

The term “and/or” includes subject matter in the alternative as well assubject matter in combination. For instance, “x and/or y” includes “x ory” and “x and y”.

The term “about” includes and describes the value or parameter per se.For example, “about x” includes and describes “x” per se. In certainembodiment, the term “about” when used in association with ameasurement, or used to modify a value, a unit, a constant, or a rangeof values, refers to variations of +1-10%. In some embodiments, the term“about” when used in association with a measurement, or used to modify avalue, a unit, a constant, or a range of values, refers to variations of+5%. In some embodiments, the term “about” when used in association witha measurement, or used to modify a value, a unit, a constant, or a rangeof values, refers to variations of +10%.

The term “between” includes and describes the value or parameter per se.For example, “between x and y” includes and describes “x” and “y” perse.

Any one of the foregoing embodiments may be combined with one or moreother embodiments disclosed herein. For instance, by combining variousembodiments disclosed herein a pharmaceutical composition comprising theratio of 4:1 insoluble to soluble corticosteroid (embodiment a) ofdexamethasone acetate/dexamethasone sodium phosphate combination(embodiment b), and sodium hyaluronate (embodiment c) in an amount of0.05% w/v and 1.5% w/v (embodiment d) is provided by this application.In another instance, by combining various embodiments disclosed herein amethod of treating inflammation and/or pain in an individual in needthereof (embodiment a) comprising injecting a pharmaceutical compositioncomprising the ratio of 4:1 insoluble to soluble corticosteroid(embodiment b) of dexamethasone acetate/dexamethasone sodium phosphatecombination (embodiment c), and sodium hyaluronate (embodiment d) in anamount of 0.05% w/v and 1.5% w/v (embodiment e) is provided by thisapplication.

The following examples further illustrate embodiments of the presentapplication. These examples are intended merely to be illustrative ofembodiments of the present application and are not to be construed asbeing limiting.

Examples Example 1 Preparation of Dexamethasone Formulation Test Samples

This example describes test samples 1-3 used in the particle size,spreadability and dissolution studies detailed in Examples 2-4.

The molecular weight of the sodium hyaluronate used in test samples 1-3is 1.56 MDa. 15 mM PBS (phosphate buffered saline) contained thefollowing reagent concentrations: 2.75 mg/mL Na₂HPO₄-7H₂O; 0.65 mg/mLNaH₂PO₄—H₂O; 7.15 mg/mL NaCl. The total volume of the samples is 3 mL.

Test No sodium hyaluronate. 15 mM PBS, dexamethasone sodium Sample 1:phosphate (2 mg), dexamethasone acetate (8 mg). Test 1.0% w/v sodiumhyaluronate, 15 mM PBS, dexamethasone Sample 2: sodium phosphate (2 mg),dexamethasone acetate (8 mg). Test 1.5% w/v sodium hyaluronate, 15 mMPBS, dexamethasone Sample 3: sodium phosphate (2 mg), dexamethasoneacetate (8 mg).

15 mM PBS was combined with sodium hyaluronate (1.0% w/v, molecularweight: 1.56 MDa), dexamethasone sodium phosphate (2 mg) anddexamethasone acetate (8 mg) to achieve a 3 mL volume. The mixture wasstirred for several hours at room temperature to allow the sodiumhyaluronate to hydrate. The resulting composition had a gel-likeconsistency and contained a suspension of dexamethasone acetateparticles. Test sample 1 did not contain any sodium hyaluronate and testsample 3 was prepared in a similar fashion as test sample 2.

Example 2 Particle Size Analysis by Optical Microscopy

This example describes a particles size study of the dispersed phase byoptical microscopy.

Test samples 1-3, described in Example 1, and samples of marketedproduct 1-3, described below, were evaluated by optical microscopy.

Test No sodium hyaluronate. 15 mM PBS, dexamethasone sodium Sample 1:phosphate (2 mg), dexamethasone acetate (8 mg). Test 1.0% w/v sodiumhyaluronate, 15 mM PBS, dexamethasone Sample 2: sodium phosphate (2 mg),dexamethasone acetate (8 mg). Test 1.5% w/v sodium hyaluronate, 15 mMPBS, dexamethasone Sample 3: sodium phosphate (2 mg), dexamethasoneacetate (8 mg). Marketed Celestone Soluspan (Betamethasone sodiumphosphate and Product 1: betamethasone acetate Injectable Suspension,USP, 6 mg/mL, Merck/Lot#043753) Marketed Depo-Medrol (Methylprednisoloneacetate Injectable Product 2: Suspension, USP, 40 mg/mL,Pfizer/Lot#H18976). Marketed Kenalog-40 (Triamcinolone AcetonideInjectable Product 3: Suspension, USP, 200 mg per 5 mL,BMS/Lot#3F75331).

A drop of test sample or the marketed product samples were placed on aclean glass slide, and covered with a cover slip. The sample slide wastransferred onto the microscopy stage, and observed at 40×magnification. A picture of representative microscopic field was taken.The size of 50 individual particles from the microscopic filed wasmeasured using Image J computer program. Note: The particle sizeaccuracy of the Image J computer program was verified usingcalibrated/standard Borosilicate Glass Microspheres with a nominalparticle size of 10 microns. The average size, and the standarddeviation of the 50 particles were calculated, and the particle sizerange was determined. A size distribution curve was generated using theparticle size data. Any other observation such as agglomeration was alsoreported for each sample.

Particle size distribution in graphical format of test samples 1-3 andmarketed products 1-3 are provided in FIGS. 1A-1F, respectively.Photomicrographs of the test samples and marketed products are shown inFIG. 2. Tables 2 and 3, below, provide details of the measurements foreach of the particles of all the evaluated samples.

TABLE 2 Particle Size Analysis of Test Samples Particle Size (microns)Particle Test Test Test number Sample#1 Sample#2 Sample#3 1 3.99 9.386.63 2 2.96 4.82 5.62 3 2.85 8.77 4.42 4 4.32 5.48 9.21 5 5.78 5.43 6.896 3.26 5.34 3.00 7 3.88 8.82 5.17 8 2.59 7.26 4.98 9 3.14 11.71 11.79 103.58 10.39 5.55 11 3.70 5.86 5.31 12 4.03 12.59 5.17 13 2.59 15.24 10.4714 3.86 5.46 13.83 15 5.24 11.26 8.30 16 2.32 5.17 8.14 17 3.31 4.217.96 18 2.65 3.14 5.05 19 3.12 3.12 6.51 20 3.46 3.70 5.18 21 3.31 4.686.30 22 2.85 4.50 6.51 23 3.46 3.70 3.70 24 4.50 4.68 4.47 25 2.67 3.884.32 26 4.68 5.51 3.26 27 2.73 3.41 4.74 28 3.38 4.82 6.99 29 3.99 3.315.63 30 2.39 15.29 4.68 31 7.16 10.22 4.98 32 5.46 8.12 5.15 33 2.527.33 4.82 34 2.67 6.43 2.67 35 3.12 7.11 4.92 36 3.64 8.95 5.34 37 2.097.35 5.34 38 2.73 5.51 7.16 39 3.00 5.78 6.19 40 3.10 5.66 4.24 41 2.523.86 4.42 42 3.75 4.36 3.05 43 3.00 4.21 5.46 44 5.97 3.52 4.74 45 5.243.23 12.93 46 4.97 11.01 12.05 47 5.18 8.95 13.39 48 6.52 8.96 7.29 495.63 7.85 11.52 50 6.00 10.07 4.65 Average size 3.78 6.79 6.40 (microns)SD 1.23 3.11 2.78 Size Range 2.09 to 7.16 3.12 to 15.29 2.67 to 13.83(microns) microns microns microns Observations Discrete particles; Fewagglomerates Few agglomerates Uniform dispersion (Picture attached)(Picture attached) (Picture attached)

TABLE 3 Particle Size Analysis of Marketed Samples Particle Size(microns) Particle Marketed Marketed Marketed number Product 1 Product 2Product 3 1 20.14 4.91 6.99 2 11.32 6.87 3.65 3 32.40 14.88 11.33 4 9.097.14 6.49 5 4.42 5.17 4.64 6 26.45 3.53 4.38 7 26.67 2.94 4.44 8 11.207.63 5.23 9 21.35 4.95 2.31 10 10.47 11.38 4.13 11 8.28 2.81 5.59 1211.26 5.89 2.94 13 18.85 3.65 4.26 14 3.14 7.87 5.28 15 12.14 3.61 4.1616 10.37 5.82 2.18 17 15.20 2.79 4.62 18 5.78 9.52 9.53 19 16.38 8.336.51 20 6.70 6.01 3.53 21 6.43 3.73 11.55 22 5.97 6.51 4.44 23 7.1610.55 7.84 24 6.11 2.55 5.10 25 48.97 3.73 2.39 26 14.57 4.83 1.63 2716.53 7.45 5.36 28 4.97 3.81 2.31 29 10.81 4.98 3.65 30 9.60 6.29 4.3631 12.93 3.47 3.28 32 12.41 2.07 1.85 33 22.03 12.33 1.63 34 11.10 7.1413.45 35 10.66 10.52 1.46 36 5.35 1.31 1.85 37 15.41 4.55 2.15 38 8.6711.84 2.96 39 9.04 2.77 4.26 40 12.59 8.43 6.73 41 9.37 1.96 4.25 429.18 4.43 12.25 43 8.75 6.01 2.63 44 9.63 6.29 2.79 45 6.82 4.59 13.5046 3.31 2.69 3.08 47 3.14 2.96 5.44 48 2.12 5.57 2.92 49 5.92 4.38 3.0850 10.02 2.81 10.22 Average size 12.02 5.73 5.01 (microns) SD 8.34 3.013.14 Size Range 2.12 to 48.97 1.31 to 14.88 1.46 to 13.50 (microns)microns microns microns Observations Wide particle size Moreagglomerates Few agglomerates distribution (Picture attached) (Pictureattached) (Picture attached)

Example 3 Spreadability Testing

This example describes the spreadability study of test samples 1-3 usingWebril Cotton Padding. Test samples 1-3 used in this study are describedin Example 1.

Test No sodium hyaluronate. 15 mM PBS, dexamethasone sodium Sample 1:phosphate (2 mg), dexamethasone acetate (8 mg). Test 1.0% w/v sodiumhyaluronate, 15 mM PBS, dexamethasone Sample 2: sodium phosphate (2 mg),dexamethasone acetate (8 mg). Test 1.5% w/v sodium hyaluronate, 15 mMPBS, dexamethasone Sample 3: sodium phosphate (2 mg), dexamethasoneacetate (8 mg).

Webril® Cotton Undercast Padding was cut from a roll into 52×38 mmdimension. The cotton padding was placed over a Teejet® water sensitivespray cards. The cotton padding along with the water sensitive card wasplaced in a closed petri plate, and labeled. A typical experimental setup is shown in FIG. 3. About 100 microliter of each sample was placedonto the cotton padding with the help of a syringe (without any needleattached) from minimal height. The dimensions of the wet zone on thecotton pad was measured using a digital caliper at 1, 3, 5, 10, 15, 30,and 45 minutes, and the surface area of wet zone at different timeinterval was calculated. The experiment was conducted in triplicate foreach sample, under room temperature. The results are summarized in FIG.4. At each time point, samples with a higher concentration of sodiumhyaluronate had smaller wet zone surface areas. For instance, 45 minutesafter applying the test samples to the cotton padding, the wet zones oftest samples 1 (no sodium hyaluronate), 2 (1.0% w/v sodium hyaluronate),and 3 (1.5% w/v sodium hyaluronate) were 229 mm², 145 mm², and 100 mm²,respectively.

The length of time for the color change on the water sensitive spraycard from yellow to blue was also noted. The time from application ofthe test sample to the appearance of blue color on the card representsthe time taken by each sample to travel from the surface of the cottonpad to its bottom. The vertical travel time for test samples 1 (nosodium hyaluronate), 2 (1.0% w/v sodium hyaluronate), and 3 (1.5% w/vsodium hyaluronate) is 1 minute, 3 minute and 10 minutes, respectively.FIG. 5 shows a photograph of the three test samples in triplicate andsummarizes the vertical travel time. This result suggests that thevertical travel time of the test samples increases with higherconcentrations of sodium hyaluronate.

Example 4 In Vitro Dissolution Study of Dexamethasone

This Example describes in vitro dissolution testing for dexamethasone intest samples 1-3 using a USP Dissolution Apparatus. Test samples 1-3used in this study are described in Example 1.

Test No sodium hyaluronate. 15 mM PBS, dexamethasone sodium Sample 1:phosphate (2 mg), dexamethasone acetate (8 mg). Test 1.0% w/v sodiumhyaluronate, 15 mM PBS, dexamethasone Sample 2: sodium phosphate (2 mg),dexamethasone acetate (8 mg). Test 1.5% w/v sodium hyaluronate, 15 mMPBS, dexamethasone Sample 3: sodium phosphate (2 mg), dexamethasoneacetate (8 mg).

About 200 mL of purified water was transferred into dissolution vessels,and allowed to attain a temperature of 37° C. About 1 gram of testsamples were transferred into sample holders, and placed into the bottomof the dissolution vessel. The study was conducted using Type 2 USPDissolution Apparatus with paddle. A typical dissolution setup is shownin FIG. 6. The medium was stirred at 25 rpm, and 3 mL samples werewithdrawn at 10 mins., 20 mins., 30 mins., 1 h, 2 h, 4 h, 6 h, and 24 h.After each sampling, 3 mL of purified water was replaced into thedissolution vessel. The samples were analyzed for the quantity ofdexamethasone sodium phosphate and dexamethasone acetate by a HPLCmethod. Note: The above method was based on the assay method ofdexamethasone sodium phosphate injection USP with modifications for thesimultaneous estimation of dexamethasone sodium phosphate anddexamethasone acetate. Dissolution profile graphs for dexamethasonesodium phosphate and dexamethasone acetate were generated consideringthe amount of drug(s) dissolved at 24 hours is equivalent to 100% labelclaim. FIG. 7 shows a plot of the percentage of dexamethasone sodiumphosphate (7A) and dexamethasone acetate (7B) dissolved as a function oftime in each of the test samples 1-3.

Virtually all of the dexamethasone sodium phosphate in test sample 1, nosodium hyaluronate, is dissolved within the measurement at 10 minutes.At 1 hour, approximately 78% of the drug in test sample 2 (1.0% w/v ofsodium hyaluronate) and approximately 42% of the drug in test sample 3(1.5% w/v of sodium hyaluronate) is dissolved. At 2 hours, all of thedrug in test sample 2 and approximately 72% of the drug in test sample 3is dissolved.

Dissolution of dexamethasone acetate requires more time than the moresoluble form of the drug. At 1 hour, approximately 68% of dexamethasoneacetate is dissolved when no sodium hyaluronate is present in theformulation, test sample 1. At 1 hour, approximately 62% of the drug intest sample 2 (1.0% w/v of sodium hyaluronate) and approximately 20% ofthe drug in test sample 3 (1.5% w/v of sodium hyaluronate) is dissolved.At 2 hours, 78% of the drug in test sample 1, 72% of the drug in testsample 2 and approximately 54% of the drug in test sample 3 isdissolved.

These results suggest that increasing amounts of sodium hyaluronateresult in a longer dissolution time of either dexamethasone sodiumphosphate or dexamethasone acetate as.

Example 5 Formulations as a Function of Sodium Hyaluronate MolecularWeight and Concentration

This example studies the effects of varying the molecular weight andconcentration of sodium hyaluronate. It provides pH and Osmolalityprofiles and centrifugation observations and extrusion forcemeasurements of the prepared formulations.

Formulations. 9 formulations were prepared using 15 mM PBS solution(3.11 mg/mL Na₂HPO₄-7H₂O; 0.47 mg/mL NaH₂PO₄—H₂O; and 6.7 mg/mL NaCl); 2mg dexamethasone sodium phosphate; 8 mg dexamethasone acetate; andsodium hyaluronate. The total volume of each formulation was 3 mL. Eachof the 9 formulations vary by the concentration and molecular weights ofthe sodium hyaluronate, as summarized in Tables 4-6. Three molecularweights of the viscosity enhancing agent were investigated: MW1 at 711kDa, MW2 at 880 kDa and MW3 at 2,650 kDa. For each of the molecularweights, MW1-MW3, three different concentrations of sodium hyaluronatewas used. The concentration as well as the measured pH and osmolalityfor each of the 9 formulations are summarized for MW1-MW3 in Tables 4-6.

TABLE 4 NaHy MW1 MW 711 kDa Concentration (%, 2.0 3.0 4.0 w/w) Target pH7.3 ± 0.3 Actual pH 7.5 7.5 7.5 Target Osmolality 285 ± 20  (mOsm/kg)Actual Osmolality 321    349    369   

TABLE 5 NaHy MW2 MW 880 kDa Concentration (%, 2.0 3.0 3.5 w/w) Target pH7.3 ± 0.3 Actual pH 7.5 7.5 7.5 Target Osmolality 285 ± 20  (mOsm/kg)Actual Osmolality 324    348    360   

TABLE 6 NaHy MW3 MW 2,650 kDa Concentration (%, 1.5 2.0 2.5 w/w) TargetpH 7.3 ± 0.3 Actual pH 7.5 7.5 7.5 Target Osmolality 285 ± 20  (mOsm/kg)Actual Osmolality 324    331    342   

Centrifugation Observations. Each of the 9 sample formulations wereplaced in a test tube and centrifuged at 3500 rpm. Observations of thesample were made at 60 min and 90 min and are summarized in Table 7below.

TABLE 7 Sample 60 min 90 min MW1-20 Visible pellet Bigger pellet mg/mLsettlement MW1-30 Slightly visible Slightly bigger mg/mL pellet MW1-40No visible No visible mg/mL settlement settlement MW2-20 Visible pelletBigger pellet mg/mL settlement MW2-30 No visible Slightly visible mg/mLsettlement pellet MW2-35 No visible No visible mg/mL settlementsettlement MW3-15 No visible No visible mg/mL settlement settlementMW3-20 No visible No visible mg/mL settlement settlement MW3-25 Novisible No visible mg/mL settlement settlement

Extrusion Force Measurements.

The extrusion force required at two test speeds, 2.36″/minute and0.5″/min, was measured for each of the 9 formulations described. Theforce measurements are summarized in Table 8. At each molecular weight,the amount of force required to achieve the test speeds increased as afunction of increasing concentration of sodium hyaluronate.

TABLE 8 Test Speed 2.36″/minute 0.5″/minute Force N lbf N lbf MW1-20mg/mL 37.5 8.4 27.7 6.2 MW1-30 mg/mL 70.0 15.8  58.1 13.1 MW1-40 mg/mLDid not perform test 97.3 21.9 MW2-20 mg/mL 39.4 8.9 29.8 6.7 MW2-30mg/mL 69.6 15.7  59.2 13.3 MW2-35 mg/mL Exceeded max. force 78.0 17.5MW3-15 mg/mL 20.6 4.6 17.3 3.9 MW3-20 mg/mL 32.9 7.4 27.2 6.1 MW3-25mg/mL 46.2 10.4  39.7 8.9

Example 6 Formulations as a Function of 1.56 MDa Sodium HyaluronateConcentration

This example studies the effects of varying the concentration of sodiumhyaluronate having a molecular weight of 1.56 MDa. It provides pH andOsmolality profiles and centrifugation observations and extrusion forcemeasurements of the prepared formulations.

7 formulations were prepared using 15 mM PBS solution (2.75 mg/mLNa₂HPO₄-7H₂O; 0.65 mg/mL NaH₂PO₄—H₂O; 7.15 mg/mL NaCl); 2 mgdexamethasone sodium phosphate; 8 mg dexamethasone acetate; and sodiumhyaluronate to achieve a 3 mL volume. The total volume of eachformulation was 3 mL. Each of the 7 formulations varied by theconcentration of the sodium hyaluronate (molecular weight 1.56 MDa). 7concentrations of the viscosity enhancing agent were investigated: 0.1%w/v, 0.25% w/v, 0.5% w/v, 0.75% w/v, 1.0% w/v, 1.25% w/v and 1.5% w/v.The measured pH and osmolality for each of the 7 formulations aresummarized in tables 9 and 10.

TABLE 9 MW & Lot # 1.56 MDa, Lot 024055 Concentration (%, 0.1 0.25 0.5w/w) Target pH 7.1 ± 0.3 Actual pH 7.0 7.0  7.0 Target Osmolality 285 ±20  (mOsm/kg) Actual Osmolality 266    269    273   

TABLE 10 MW & Lot # 1.56 MDa, Lot 024055 Concentration (%, 0.75 1.0 1.251.5 w/w) Target pH 7.1 ± 0.3 Actual pH 7.0  7.0 7.0  7.0 TargetOsmolality 285 ± 20  (mOsm/kg) Actual Osmolality 284    287    291   308   

Centrifugation Observations.

Each of the 7 sample formulations were placed in a test tube andcentrifuged at 3500 rpm at room temperature. Observations of the sampleswere made at 30 min., 90 min., 180 min., 270 min., and 360 min and aresummarized in Table 11. Photographs of the test tubes were taken at 90minutes and 360 minutes and are shown in FIGS. 10 and 11.

TABLE 11 Sample 30-min. 90-min. 180-min. 270-min. 360-min. 0.1% CompleteComplete Complete N/A N/A separation separation separation w/big w/bigw/big pellet pellet pellet 0.25%  Complete Complete Complete N/A N/Aseparation separation separation w/big w/big w/big pellet pellet pellet0.5% Some Complete Complete N/A N/A separation separation separationw/big w/big w/big pellet pellet pellet 0.75%  Some Some SeparationComplete Complete separation, separation w/ w/bigger separationseparation visible visible pellet w/big w/big pellet pellet pelletpellet 1.0% Small Visible Bigger Bigger Big pellet pellet pellet pelletpellet 1.25%  No pellet No pellet Slight Bigger Pellet pellet pellet1.5% No pellet No pellet No pellet Slight Visible pellet pellet

Extrusion Force Measurements.

The extrusion force required at test speed 0.5″/min, was measured foreach of the 7 formulations described. Increasing concentrations ofsodium hyaluronate resulted in increasing amounts of extrusion forcerequired to achieve the test speed. The force measurements aresummarized in Table 12.

TABLE 12 Test Speed 0.5″/minute Concentration (%) N lbf 0.10 0.25 0.504.93 1.1 0.75 7.28 1.6 1.00 10.27 2.3 1.25 15.33 3.4 1.50 20.87 4.7

Example 7 Calculated Estimates for Physical Properties of Formulations

Stoke's Law was used to calculate various physical properties as afunction of particles size and viscosities.

Stoke's Law: V=gd ²(Σ_(p)−ρ_(f))/18

V=Velocity in cm/sg=gravitational acceleration in cm/s²d=diameter of spherical particle in cmρ_(p)=density of particle in g/cm³ρ_(f)=density of suspending media in g/cm³η=viscosity of suspending media in poises (g/cm-s)

Based on the parameters summarized below, the estimated minimum zeroshear viscosity for particle sizes 8 μm and 5 μm to settle at a rate ofless than or equal to 1 mm in 2 years is summarized below.

g (cm/s²) = 980.665 ρ_(p) (g/cm³) ≈ 1.261 ρ_(f) (g/cm³) ≈ 1.01 d (μm) =8 Estimated minimum zero shear viscosity to settle ≦ 1-mm in 2-year:≧552 (kcP) g (cm/s²) = 980.665 ρ_(p) (g/cm³) ≈ 1.261 ρ_(f) (g/cm³) ≈1.01 d (μm) = 5 Estimated minimum zero shear viscosity to settle ≦ 1-mmin 2-year: ≧216 (kcP)

Three molecular weights of the viscosity enhancing agent wereinvestigated: MW1 at 711 kDa, MW2 at 880 kDa and MW3 at 2,650 kDa. Foreach of the molecular weights, MW1-MW3, three different concentrationsof sodium hyaluronate was used. The 9 formulations are summarized forMW1-MW3 in tables 4-6 of Example 5 and the predicted settling rates aresummarized in Tables 13-15.

TABLE 13 Predicted number of days for 1 mm settle; Zero shear viscosityand estimated time for 8 μm particles. MW MW1 MW2 MW3 711 kDa 880 kDa2,650 kDa mg/ml 20 30  40 20  30  35  15 20 25 η (kcP) 25 98 253 49 202348  769 2,420 5,502 V (cm/s) 3.6E−08 9.0E−09 3.4E−09 1.8E−08 4.3E−092.5E−09 1.1E−09 3.6E−10 1.6E−10 Days for 1- 33 129  335 64 268 461 10173200 7276 mm Settle

TABLE 14 Predicted number of days for 1 mm settle; Viscosity @ 0.3/s andestimated time for 8 μm particles. MW MW1 MW2 MW3 711 kDa 880 kDa 2,650kDa mg/ml 20 30  40 20  30  35  15  20  25 η (kcP) 16 77 209 39 159 269205 426 652 V (cm/s) 5.3E−08 1.1E−08 4.2E−09 2.2E−08 5.5E−09 3.2E−094.3E−09 2.1E−09 1.3E−09 Days for 1- 22 102  276 52 211 356 271 563 862mm Settle

TABLE 15 Predicted number of days for 1 mm settle; viscosity @ 1/s andestimated time for 8 μm particles. MW MW1 MW2 MW3 711 kDa 880 kDa 2,650kDa mg/ml 20 30  40 20  30  35 15  20  25 η (kcP) 15 67 171 33 124 19499 196 295 V (cm/s) 5.8E−08 1.3E−08 5.1E−09 2.6E−08 7.1E−09 4.5E−098.9E−09 4.5E−09 3.0E−09 Days for 1- 20 88 226 44 163 257 131  260 390 mmSettle

FIG. 8 shows the relationship between viscosity and shear force ascalculated for the various samples. The results show that as increasingshear is applied to the sample, the measured viscosity decreases, andsuggests that high viscosity samples are relatively easy to inject.

Example 8 Calculated Estimates for Physical Properties of Formulations

Stoke's Law was used to calculate various physical properties.

Based on the parameters summarized below, the estimated minimum zeroshear viscosity for particle sizes 8 μm and 5 μm to settle at a rate ofless than or equal to 1 mm in 2 years is summarized below.

g (cm/s²) = 980.665 ρ_(p) (g/cm³) ≈ 1.261 (Crystal Steroid) ρ_(f)(g/cm³) ≈ 1.01 d (μm) = 8 (Crystal Steroid) Estimated minimum zero shearviscosity to settle ≦ 1-mm in 2-year: ≧552 (kcP) g (cm/s²) = 980.665ρ_(p) (g/cm³) ≈ 1.299 (Sanofi Steroid) ρ_(f) (g/cm³) ≈ 1.01 d (μm) = 5(Sanofi Steroid) Estimated minimum zero shear viscosity to settle ≦ 1-mmin 2-year: ≧248 (kcP)

Varying concentration of sodium hyaluronate having a molecular weight of1.56 MDa was investigated. 7 concentrations of the viscosity enhancingagent were investigated: 0.1% w/v, 0.25% w/v, 0.5% w/v, 0.75% w/v, 1.0%w/v, 1.25% w/v and 1.5% w/v. The 7 formulations are summarized in tables9 and 10 and described in Example 6, and the predicted settling ratesare summarized in tables 16-22.

TABLE 16 Predicted number of days for 1 mm settle; Zero shear viscosityand estimated time for 5 μm particles at 25° C. 1.56 MDa, Lot 024055NaHy (%) 0.1 0.25 0.5 0.75 1.0 1.25 1.5 η (kcP) Not  6 18 24  81 158 V(cm/s) Tested 6.4E−08 2.2E−08 1.6E−08 4.9E−09 2.5E−09 Days for 1- 18 5371 238 464 mm Settle

TABLE 17 Predicted number of days for 1 mm settle; Zero shear viscosityand estimated time for 5 μm particles at 5° C. 1.56 MDa, Lot 024055 NaHy(%) 0.75 1.0 1.25* 1.5 η (kcP)  40  70 116*  388 V (cm/s) 9.83E−095.66E−09 3.39E−09 1.01E−09 Days for 1- 118 205 341* 1141 mm Settle *There-test results at 25° C. indicated that 1.25% sample had viscositydecrease, but others did not.

TABLE 18 Predicted number of days for 1 mm settle; Zero Shear Viscosityand temperature for 5 μm particles, varying sodium hyaluronateconcentration from 0.75% w/v to 1.50% w/v. 0.75% 1.00% 1.25% 1.50% 25°C. η (cP) 18,060 24,065  81,047 157,900 Days for 53 71    238 464 1 mmsettle  5° C. η (cP) 40,060 69,555 116,133 388,100 Days for 118 205   341* 1141 1 mm settle *The re-test results at 25° C. indicated that1.25% sample had viscosity decrease, but others did not.

TABLE 19 Predicted number of days for 1 mm settle; Viscosity @ 0.3/s andestimated time for 5 μm particles at 25° C., varying sodium hyaluronateconcentration from 0.1% w/v to 1.50% w/v. 1.56 MDa, Lot 024055 NaHy (%)0.1 0.25 0.5 0.75 1.0 1.25 1.5 η (kcP) Not 1  7 21  49  90 V (cm/s)Tested 3.2E−07 5.5E−08 1.8E−08 8.1E−09 4.4E−09 Days for 1- 4 21 63 143266 mm Settle

TABLE 20 Predicted number of days for 1 mm settle; Viscosity @ 0.3/s andestimated time for 5 μm particles at 5° C., varying sodium hyaluronateconcentration from 0.1% w/v to 1.50% w/v. 1.56 MDa, Lot 024055 NaHy (%)0.75 1.0 1.25* 1.5 η (kcP) 16  45  62* 181 V (cm/s) 2.40E−08 8.75E−096.32E−09 2.17E−09 Days for 1- 48 132 183* 532 mm Settle *The re-testresults at 25° C. indicated that 1.25% sample had viscosity decrease,but others did not.

TABLE 21 Predicted number of days for 1 mm settle; Viscosity @ 1/s andestimated time for 5 μm particles at 25° C., varying sodium hyaluronateconcentration from 0.1% w/v to 1.50% w/v. 1.56 MDa, Lot 024055 NaHy (%)0.1 0.25 0.5 0.75 1.0 1.25 1.5 η (kcP) Not 1  6 16 33  57 V (cm/s)Tested 3.4E−07 6.9E−08 2.5E−08 1.2E−08 6.9E−09 Days for 1- 3 17 47 97168 mm Settle

TABLE 22 Predicted number of days for 1 mm settle; Viscosity @ 1/s andestimated time for 5 μm particles at 5° C., varying sodium hyaluronateconcentration from 0.75% w/v to 1.50% w/v. 1.56 MDa, Lot 024055 NaHy (%)0.75 1.0 1.25* 1.5 η (kcP) 12 29  40*  98 V (cm/s) 3.38E−08 1.38E−089.96E−09 4.01E−09 Days for 1- 34 84 116* 289 mm Settle *The re-testresults at 25° C. indicated that 1.25% sample had viscosity decrease,but others did not.

FIG. 9 shows the relationship between viscosity and shear force ascalculated for various formulations as a function of sodium hyaluronateconcentration (MW 1.56 MDa). The results show that as increasing shearis applied to the sample, the measured viscosity decreases, and suggeststhat high viscosity samples are relatively easy to inject.

What is claimed is:
 1. An aqueous pharmaceutical composition comprisingan insoluble corticosteroid; a soluble corticosteroid; and at least oneviscosity enhancing agent; wherein the insoluble form of thecorticosteroid has an average particle size of less than 10 μm.
 2. Anaqueous pharmaceutical composition comprising an insolublecorticosteroid; a soluble corticosteroid; and at least one viscosityenhancing agent; wherein the pharmaceutical composition has a viscosityof between 1 kcP and 200 kcP.
 3. The aqueous pharmaceutical compositionof claim 1, wherein the insoluble and soluble corticosteroid is selectedfrom the group consisting of dexamethasone, methylprednisolone,prednisolone, triamcinolone acetonide, betamethasone, and salts andesters thereof.
 4. The aqueous pharmaceutical composition of claim 1,wherein the soluble corticosteroid is selected from the group consistingof dexamethasone sodium phosphate, methylprednisolone sodium succinate,prednisolone sodium succinate, triamcinolone acetonide phosphate ester,betamethasone sodium phosphate; and the insoluble corticosteroid isselected from the group consisting of dexamethasone acetate,methylprednisolone acetate, prednisolone acetate, triamcinoloneacetonide acetate and betamethasone acetate.
 5. The aqueouspharmaceutical composition of claim 1, wherein the solublecorticosteroid is dexamethasone sodium phosphate and the insolublecorticosteroid is dexamethasone acetate.
 6. The aqueous pharmaceuticalcomposition of claim 1, wherein the at least one viscosity enhancingagent is selected from the group consisting of sodium hyaluronate,hyaluronic acid, cross-linked hyaluronic acid, polyvinylpyrrolidone,hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxethylcellulose, and glycerol.
 7. The aqueous pharmaceutical composition ofclaim 1, wherein the ratio of soluble corticosteroid to insolublecorticosteroid ranges from about 1:4 to 4:1.
 8. The aqueouspharmaceutical composition of claim 1, wherein the viscosity enhancingagent is less than 2% w/v.
 9. The aqueous pharmaceutical composition ofclaim 1, further comprising a preservative and/or an anesthetic.
 10. Theaqueous pharmaceutical composition of claim 2, wherein the insoluble andsoluble corticosteroid is selected from the group consisting ofdexamethasone, methylprednisolone, prednisolone, triamcinoloneacetonide, betamethasone, and salts and esters thereof.
 11. The aqueouspharmaceutical composition of claim 2, wherein the solublecorticosteroid is selected from the group consisting of dexamethasonesodium phosphate, methylprednisolone sodium succinate, prednisolonesodium succinate, triamcinolone acetonide phosphate ester, betamethasonesodium phosphate; and the insoluble corticosteroid is selected from thegroup consisting of dexamethasone acetate, methylprednisolone acetate,prednisolone acetate, triamcinolone acetonide acetate and betamethasoneacetate.
 12. The aqueous pharmaceutical composition of claim 2, whereinthe soluble corticosteroid is dexamethasone sodium phosphate and theinsoluble corticosteroid is dexamethasone acetate.
 13. The aqueouspharmaceutical composition of claim 2, wherein the at least oneviscosity enhancing agent is selected from the group consisting ofsodium hyaluronate, hyaluronic acid, cross-linked hyaluronic acid,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxethyl cellulose, and glycerol.
 14. The aqueouspharmaceutical composition of claim 2, wherein the ratio of solublecorticosteroid to insoluble corticosteroid ranges from about 1:4 to 4:1.15. The aqueous pharmaceutical composition of claim 2, wherein theviscosity enhancing agent is less than 2% w/v.
 16. The aqueouspharmaceutical composition of claim 2, further comprising a preservativeand/or an anesthetic.
 17. A method for treating inflammation and/or painin an individual in need thereof, comprising injecting an aqueouspharmaceutical composition into the individual, wherein the formulationcomprises an insoluble corticosteroid; a soluble corticosteroid; and atleast one viscosity enhancing agent.
 18. The method of claim 17, whereinthe aqueous pharmaceutical composition is injected into the epiduralspace.
 19. The method of claim 17, wherein less than 20 N of force isused to inject the aqueous pharmaceutical composition into the epiduralspace at a rate of about 0.5″/min.
 20. The method according to claim 17,wherein the individual is injected with the aqueous pharmaceuticalcomposition once every 4 to 24 weeks.
 21. A syringe comprising theaqueous pharmaceutical composition of claim 1.